'Shapeshifting' cancer cells promote metastasis

Using innovative techniques and a wide range of experiments, researchers have demonstrated that prostate cancer cells have the ability to alter their shape, thereby promoting metastasis.

Cancer is a complex beast. It is difficult to treat when it is present in one location, but when it moves to other parts of the body in a process called metastasis, it becomes even more problematic.

Prostate cancer, for instance, can travel to any part of the body. Most commonly, it travels through the blood or lymphatic vessels into bones, but it can also reach the lymph nodes, lungs, liver, and brain, among other locations.

Understanding how a tumor migrates and puts down roots in distant locations is the subject of much research. Cancer's ability to flourish in foreign tissues involves a complex set of steps - for instance, it needs to be able to survive the journey to a new location, securely link to a new tissue type, and generate new blood vessel growth to supply it with nutrients.

Cytoskeleton and metastasis

One area of focus has been the role of the actin cytoskeleton in metastasis. The cytoskeleton is present in all cells; it consists of a complex interlinked mesh that supports the cell and helps it to maintain its shape, even under pressure.

The cytoskeleton also helps to keep the internal structures within each cell in their proper places, as well as contract to change the cell's shape and allow it to migrate. One constituent of the cytoskeleton is actin microfilaments, which are made up of long strings of the protein actin.

Recently, the actin cytoskeleton has also been implicated in cancer cell migration. A new study, published in the journal Nature Communications, takes a look at the relationship between the cytoskeleton and metastasis in more depth.

A team of researchers from Johns Hopkins Kimmel Cancer Center in Baltimore, MD, took public data from five studies on prostate cancer, the information from which included details about the chemistry and genetics of hundreds of metastatic and primary cancers, or those that had not metastasized.

AIM1's role

Of particular interest was a gene called absent in melanoma 1 (AIM1). They found that the protein that AIM1 makes was absent in 20 to 30 percent of prostate cancers that did not travel to other parts of the body, and in 40 percent of cancers that did spread.

Also, in metastatic prostate cancers, there was between two and four times less AIM1, compared with cancers that remained in the prostate.

Although AIM1 has previously been implicated in the development of melanoma, its role was not understood.

"Our experiments show that loss of AIM1 proteins gives prostate cancer cells the ability to change shape, migrate, and invade. These abilities could allow prostate cancer cells to spread to different tissues in an animal and presumably a person."

Michael Haffner, Ph.D., Johns Hopkins University

AIM1 is not the only molecule involved in the complex process of metastasis, but, as Dr. Haffner says, "[...] it appears to be a significant part of it in some cases."

Aside from the differences in quantity of AIM1, by tracking the protein with dye, the researchers also found changes in the way that the protein was positioned within the cell. They showed that in normal, noncancerous prostate cells, the AIM1 protein sat along the outside border of the cell and was paired with beta-actin, which is a component of the cell's cytoskeleton.

However, in prostate cancer cells, the protein was not found near the borders of the cells and was not paired with beta-actin.

This altered position was seen in human tissue samples, including 81 normal prostates, 87 primary prostate cancers, and 52 prostate cancers that had metastasized to lymph nodes.

Dr. Vasan Yegnasubramanian, Ph.D. - an associate professor at the Kimmel Cancer Center - explains, "It appears that when AIM1 protein levels drop, or when it's abnormally spread throughout the cell instead of confined to the outer border, the prostate cancer cells' scaffolding becomes more malleable and capable of invading other tissues."

Their theory is that when AIM1 is present, the cells' scaffolding keeps it rigid and correctly shaped. Without AIM1, the cells can become shapeshifters, capable of migrating to distant locations and slotting into new positions.

Charting cancer cells' movements

To explore how these shapeshifting cells moved, the scientists teamed up with Steven An, Ph.D., an expert in cellular mechanics. By using state-of-the-art quantitative single-cell analyses, he was able to investigate the properties of the cytoskeletons of AIM1-lacking prostate cancer cells.

This dive into the nitty gritty of cellular mechanics showed that cells without AIM1 remodeled their cytoskeleton twice as often as cells with normal AIM1 levels. They also exerted three to four times more force on the cells next to them than those with standard AIM1 levels.

These are the types of properties that could help a cell to migrate and invade other tissues. This observation was backed up by a further experiment, which showed that prostate cells with low AIM1 were found to easily migrate to empty spaces on a culture dish and infiltrate connective tissue-like materials four times quicker than cells with normal AIM1 levels.

AIM1 in mice tissue

As a further demonstration of the importance of the AIM1 protein in tumor migration, the team turned to a mouse model. They implanted prostate cancer cells without AIM1 into five mice. The cells were shown to spread to other tissues up to 100 times more than cells with standard AIM1 levels.

It is important to note that, although the cells with reduced AIM1 could successfully travel around the mouse's body, they could not establish full colonies in these locations. This demonstrates that AIM1 depletion is only part of the story, and that there is still much to understand.

As Prof. Yegnasubramanian says, "AIM1 may help prostate cancer cells disseminate throughout the body, but something else may be helping them form full-blown metastatic tumors when they get there."

The team plans to continue their work in this field, investigating other proteins that might also be involved.